And yes $295 is a lot of money, but what is the cost of all the supplements I take each month? That adds up real fast too.

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That's exactly how I felt...had done 23andMe, so knew my predispositions. But wanted to know what's actually going on in my body before making a treatment decision, so did HDRI as well. No point in running really fast down the wrong road...

Getting a high dose in the serum thus diffusing it into the CNS, I figured that would apply to mfolate too. So, unlike you, I say: if I stay on high doses for a long time, some healing might occur, and in time I may feel better. I don't expect healing in the CNS will make me "suddenly feel much better". Slowly and gradually are the words when I think of healing in the CNS.
I could be wrong of course.

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But this is only true if you accept the premise that there is something in the CNS that needs "healing". And I'm not sure that there is. At least not for all of us. What exactly are we talking about here? Increased synaptogenesis? Axonal regrowth? Sure, if there is some neuropathy present, high doses might help, but are there? If the problem is massive inflammation, I do not see how high folate doses will heal anything.

The current evidence points to ME being of an autoimmune nature, and high folate is not likely to improve that, to my knowledge. Methylation is important, because it affects epigentics, so it can silence gene mutations. This could be very valuable for us. But that is a far cry from high doses of folate (or b12). Do you have any theory of what causes your symptoms, and why high dose folate/b12 will help?

And yes $295 is a lot of money, but what is the cost of all the supplements I take each month? That adds up real fast too.

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Well, the price would be double that for me. Still, it would be useful information. But I think we are kidding ourselves if we think we do not want a follow up test to see if we're getting the results we want.

But this is only true if you accept the premise that there is something in the CNS that needs "healing". And I'm not sure that there is. At least not for all of us. What exactly are we talking about here? Increased synaptogenesis? Axonal regrowth? Sure, if there is some neuropathy present, high doses might help, but are there? If the problem is massive inflammation, I do not see how high folate doses will heal anything.

The current evidence points to ME being of an autoimmune nature, and high folate is not likely to improve that, to my knowledge. Methylation is important, because it affects epigentics, so it can silence gene mutations. This could be very valuable for us. But that is a far cry from high doses of folate (or b12). Do you have any theory of what causes your symptoms, and why high dose folate/b12 will help?

For the time being I relate all my symptoms during more than twenty years of illness to B12 deficiency. Nerve problems in body (tingling) and problems in brain (speech, coordination, memory, concentration), multiple pulmonary embolisms (when having a severe cytomegalovirus infection), fatigue - among many other things.

As soon as my doctor learned of the low B12 serum, a slightly elevated homocysteine, and the C677T, the diagnosis ME/CFS was out of the window and exchanged for B12 deficiency. The symptoms I have (and had) fit in a B12 deficiency. Besides, in the Netherlands you only have ME/CFS when everything else is ruled out, you can't have both ME/CFS and something else that's causing fatigue, like B12 deficiency for instance (which imo doesn't necessarily have to be true).

In my country doctors, familiar with B12 issues, say that progress can be made within the first two years after starting with 1 mg B12 injections IM - not being cyanoB12. B12 is considered safe, taking too much of B12 is being seen as just a waste of money.
Normally the schedule of injecting is 5 or 10 weeks twice a week, and after that people are advised to go by their symptoms (inject less frequent when having no symptoms, inject more often when having symptoms) provided that they follow the life long minimal maintenance regime of one injection every three months when no cause of the B12 deficiency is found, or when the cause can not be treated.
When having neurological problems like tingling sensations in arms/legs, progress is reported when following a more intense schedule of twice a week for two years. After that period of two years no more improvement is thought to happen. *

So, that medical information was my basis.
I am in my first year of supplementing B12. At the start, because of my neurological symptoms, I wanted to do the intense treatment of 1 mg injection twice a week for two years, at the least.

Reading Freddd's theory that simply avoiding symptoms (which imo is basically the Dutch approach when on the maintenance regime) won't give a 100% recovery, made sense to me.
His theory fits right into my thinking, and in the knowledge I gathered: more + longer = better outcome, better chance of healing.

I really think that in normal circumstances lots of B12 or methylfolate can't hurt. Trouble is of course people do not know whether they are in a normal circumstance.
Maybe I am. Maybe I have no other issues besides B12 deficiency and C677T. I responded well to mB12 and methylfolate when starting supplementing them, so they are useful. To what extent remains to be seen.

In conclusion.
You ask me why a high dose will help (me). I ask thee, dear adreno, in return: seeing my diagnosis, my history, the medical information I got, why should I keep my doses low?

Edit:
* After those two years of injecting twice a week returning to the normal maintenance schedule is advised (when no cause is found, or when the cause can not be treated).

In conclusion.
You ask me why a high dose will help (me). I ask thee, dear adreno, in return: seeing my diagnosis, my history, the medical information I got, why should I keep my doses low?

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Well, you shouldn't be listening to an old cynical man (me) anyways. So carry on

What can I say other than "healing" used as a term without operationalization is just hippie-speak to me. I do not agree with the idea that neurological disorders (in general) can be reduced to a deficiency of any kind. Your symptoms may indicate B12 deficiency, but as they are unspecific they could be due to many other causes as well.

Do I recommend low dosages of folate? No. I recommend balance. Overdriving your methylation cycle (and perhaps losing glutathione in the process) is not going to improve things. Just my opinion. Others recommend the "more is better" approach. But, in this casino royale of health you place your money and make your bets...

What can I say other than "healing" used as a term without operationalization is just hippie-speak to me. I do not agree with the idea that neurological disorders (in general) can be reduced to a deficiency of any kind. Your symptoms may indicate B12 deficiency, but as they are unspecific they could be due to many other causes as well.

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I've started this road, and I'll see where it leads to, maybe it's got a dead end.
Also, I definitely do not exclude having several diseases or disorders at the same time. I just don't investigate other possibilities right now. (As far as those are concerned I am merely sitting back and observing what you're doing )

Adrenals, thryroid... Sure, there could be something that does not come up with regular testing, but doctors here are not willing to test everything there's to test, and without doctors help, getting specific results is difficult, a hassle, as is in your country apparently (whenever I think of you in the tundras I think of Russia, or Iceland...)

Do I recommend low dosages of folate? No. I recommend balance. Overdriving your methylation cycle (and perhaps losing glutathione in the process) is not going to improve things. Just my opinion. Others recommend the "more is better" approach, but I disagree with this. But, in this casino royale of health you place your money and make your bets...

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O great. If that was meant to cheer me up...? I was never good in making bets.

Balance is good; I am not planning on staying high forever... I am looking for heaven somewhere up there right now, but I think 2400 or 3200 mcg of mfolate is certainly a nice dose for me as well (after having reached the sky, that is).

Well, the price would be double that for me. Still, it would be useful information. But I think we are kidding ourselves if we think we do not want a follow up test to see if we're getting the results we want.

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Oh I agree a follow-up is necessary. But I would wait until some sort of steady state on scale of a few months or more.

Balance is good; I am not planning on staying high forever... I am looking for heaven somewhere up there right now, but I think 2400 or 3200 mcg of mfolate is certainly a nice dose for me as well (after having reached the sky, that is).

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I don't think 2400-3200 mcg of methylfolate split up over a day is excessive or even all that high especially if you have the mutations that support a need for methylfolate. But I don't think at those doses you will get much in the way of CNS saturation.

Remember doctors routinely give people scrips for 4000 mcg of folic acid (uggh for other reasons) or even now similar amounts of folinic acid. Methylfolate is a better functional form for sure and yet is a pain in the *bleep* with regards to half-life but again those doses of 2400 or so are not excessive. You have to ind what works for you.

Just because I get smacked going to 1600 mcg should not sway other people one way or the other. On the other hand, while people like Freddd have had undenialbe successes on large dose of methylfolate, people still need to find their own place on the curve.

Personally, I am on these forums, yes, but my MTHFR gene is for the most part wild type. According to Rich Vank (and I agree with him), I don't even have CFS / ME. Back in 2010 my NutraEval results were so horrifically different and exotic, Rich had a hard time framing what the heck was going on. Still I just ended up with some of the same issues as CFS / ME but coming down a very different road.

I just think the doses of folinic acid in that 81% paper are really high and some others on here who are intentionally driving methylfolate into the CNS to affect neurological symptoms, that may not be for everyone. I think my "water wheel" analogy while maybe a bit simplistic is pretty accurate.

I don't think 2400-3200 mcg of methylfolate split up over a day is excessive or even all that high especially if you have the mutations that support a need for methylfolate.

Remember doctors routinely give people scrips for 4000 mcg of folic acid (uggh for other reasons) or even now similar amounts of folinic acid. Methylfolate is a better functional form for sure and yet is a pain in the *bleep* with regards to half-life but again those doses of 2400 or so are not excessive. You have to ind what works for you.

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dbkita, do you know which mutations indicate that folinic acid won't work effectively for someone, as opposed to those that prevent folic acid from being converted?

I don't think 2400-3200 mcg of methylfolate split up over a day is excessive or even all that high especially if you have the mutations that support a need for methylfolate. But I don't think at those doses you will get much in the way of CNS saturation.

Remember doctors routinely give people scrips for 4000 mcg of folic acid (uggh for other reasons) or even now similar amounts of folinic acid. Methylfolate is a better functional form for sure and yet is a pain in the *bleep* with regards to half-life but again those doses of 2400 or so are not excessive. You have to ind what works for you.

Just because I get smacked going to 1600 mcg should not sway other people one way or the other. On the other hand, while people like Freddd have had undenialbe successes on large dose of methylfolate, people still need to find their own place on the curve.

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I did a quick search on the effects of methylfolate before going to 12 tablets yesterday (9600 mcg). I learned there are people taking 30 mg or even 40 mg a day. As to side effects, apart from allergic reactions, I learned it is considered reasonably safe (GI problems).

Reason I think 2400-3200 mcg might be a nice dose some time in future is because it was mentioned on mthfr.net by Ben Lynch that most people with C677T felt good with 3200 mcg a day.
But sure, you are right, I have to find what works for me. I'm in a experimental phase now, checking what feels good, better and worse, where my max is and where the minimal needed intake. So what I consider to be a nice dose some time in future might very well change some time in future.

If all goes well this week I'll increase my amount next Friday again. And with every increase of methylfolate I'll take another look at my mB12 and aB12 intake (and electrolytes intake), because balance is good - balance is key.

What do you think might be the dose that is needed to be of any benefit to the CNS, dbkita?

I just think the doses of folinic acid in that 81% paper are really high and some others on here who are intentionally driving methylfolate into the CNS to affect neurological symptoms, that may not be for everyone. I think my "water wheel" analogy while maybe a bit simplistic is pretty accurate.

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I like it. I have used the term fly wheel at home. I put a lot of supplements in, so to get the wheel going, once it's turning, I can cut back my intake.

dbkita, do you know which mutations indicate that folinic acid won't work effectively for someone, as opposed to those that prevent folic acid from being converted?

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Rich Vank and others believed that SHMT1 and MTHFS would be the enzymes in question given they are the only two known to interaction in production or conversion of folinic acid. There is a thread on here that suggest possible SNPs. But to me it is not clear we really know what haplotype is at risk. So not sure anyone really knows which mutations.

I did a quick search on the effects of methylfolate before going to 12 tablets yesterday (9600 mcg). I learned there are people taking 30 mg or even 40 mg a day. As to side effects, apart from allergic reactions, I learned it is considered reasonably safe (GI problems).

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Sure it is safe and non-toxic. No arguments. But its secondary impacts on physiology are massive when complemented with mb12 and other cofactors. If you want to learn more, read up on DNA methylation. Methylation is one of the master control lever for gene transcription and protein expression. Methylation can often silence gene expression. For some at high levels this is an essential characteristic. For others there can be too much suppression. This is besides the impact on production of carnitine, creatine, conversion of histidine, neurotransmitter production and catabolism and oodles of other functions.

Reason I think 2400-3200 mcg might be a nice dose some time in future is because it was mentioned on mthfr.net by Ben Lynch that most people with C677T felt good with 3200 mcg a day.

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Ben Lynch has an elaborate titration protocol and only recommends those amounts for people who are strictly homozygous C677T. Oddly enough many people who on these forums are NOT homozygous C677T. So not sure what to say.

But sure, you are right, I have to find what works for me. I'm in a experimental phase now, checking what feels good, better and worse, where my max is and where the minimal needed intake. So what I consider to be a nice dose some time in future might very well change some time in future.

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If you find a good happy place. I would stay there for a lot longer than a few weeks before tinkering. Methylation is so profound you need to give the body time to adjust and reach homeostatis imo.

What do you think might be the dose that is needed to be of any benefit to the CNS, dbkita?

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I will defer to Freddd and other on this matter. While I have a CNS autoimmune disease, I don't have many of the more neurological symptoms reported on these boards, so I have no experience with such high doses.

Personally my homocysteine for example and MCV were BETTER before methylation supplementation of any type for what it is worth. That is why I place more stock in clinical symptoms as opposed to individual biomarkers. On the other hand if I drop down further on methylfolate then I lose a lot of eneryg, joie de vive and drive.

I wish I could go higher but again potassium excretion crumples me. At 800 mcg FolaPro, 17.5 mg p5p, and 100 mg riboflavin, I now excrete 40%% the amount of potassium I did last summer while on additional 800 mcg l5mthf, 500 mg TMG, raise to 50 mg p5p, 100 mg r5p and 200 mg SAMe.

My intake of potassium has fallen from 10-11 grams with hypokalemia to 6-7 grams with healthy serum potassium levels ~3.7-3.8. In the high methylation scenario I was dumping 250 mEq per 24 hours in the toilet which is about 10 grams. So intake barely was higher than excretion and serum potassium went to 2.8-2.9 at its worst. Now I excrete slightly more than 100 mEq in 24 hours or roughly 4 grams but ingest 6-7 grams. You see the significance, right? (note: some potassium is also lost via defecation, nor is all that is ingested absorbed).

As I have told others needing to intake whether by food or supplements greater than 7-8 grams of K+ per day, is in my mind an untenable electrolyte situation. Though I must admit Paleolithic man had high intake of potassium and low intake of sodium (<700 mg per day) compared to modern man, please remember their mineralcorticoids and ATP pumps worked well or they died. Period. So such comparisons are kind of hard to make. Then again Paleolithic man never made it to my age anyways

I was taking only ~ 25-50 mcg of methylfolate and getting euphoria (COMT++, MAO A++) when the side effects weren't wiping me out. I suppose it could have just triggered something else, but does that suggest that amount could have passed the BBB? I guess there is no way to know, but apparently even doses that small can trigger something to happen in the CNS.

Sure it is safe and non-toxic. No arguments. But its secondary impacts on physiology are massive when complemented with mb12 and other cofactors. If you want to learn more, read up on DNA methylation. Methylation is one of the master control lever for gene transcription and protein expression. Methylation can often silence gene expression. For some at high levels this is an essential characteristic. For others there can be too much suppression. This is besides the impact on production of carnitine, creatine, conversion of histidine, neurotransmitter production and catabolism and oodles of other functions.

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Hi dbkita!

What do you consider to be a high level?

Thanks for mentioning these keywords. DNA methylation and silencing gene expression brought me to a wondrous world I didn’t know. I must say, after googling I’m feeling less worried. Although I did not succeed in doing years of study in one single day, so it could well be I’m missing vital information.

I agree methylation has an impact, but I have difficulty relating massive impacts solely to high intakes of mfolate, mb12 and cofactors. Yes, sure, high intakes have an impact if you have a shortage. But shortage itself may often lead to local or even global hypermethylation. (Hahaha! Hear me, how I sound! Forgive me, just think: the more ignorant, the more arrogant. )

Compared to global hypermethylation global hypomethylation seems to be more risky to me; “genomic instability and loss of heterozygosity” increase the risk of cancer, and genomic demethylation (demethylating drugs) “can have serious side effects and even promote malignant transformations of genes”.

What I learned: global hypomethylation (of the entire genome) often is accompanied by local hypermethylation. And I think (but it could well be I’m confusing things ATM) there’s no such thing as a simple ‘I’m overmethylating’ or ‘I’m undermethylating’ (not alluding to anyone in particular).
When having cancer for instance, there’s often (always?) localised hypermethylation and genome-wide hypomethylation.

Here are some quotes I gathered:

“Undermethylation of the entire genome is referred to as global hypomethylation. Global hypomethylation combined with over methylation of highly select repeated regions of the gene is associated with both aging and cancer. Both undermethylation of tumor-causing genes, where the genes are not turned off, and overmethylation of tumor-suppressing genes, where the genes are turned off, contribute to cancer development.”
“Folate deficiency has been shown to result in both hypo- and hyper–gene-specific methylation. (…) However, with continued folate deficiency, an increase in both p53 and genome-wide methylation was seen.”
“Selenium deficiency decreased DNA methylation in Caco-2 cells and in rat liver and colon. In contrast, vitamin C deficiency has been associated with DNA hypermethylation in lung cancer cells.”
“Retinoic acid [excess] leads to global hypomethylation but region-specific hypermethylation”

What’s causing changes in methylation? Well, IMHO it definitely isn’t just a matter of taking different amounts of B12, methylfolate and cofactors.
“Different nutrients can have different effects on methylation.” Diets high in fat, for instance, negatively affect methylation. I have read that nutrients can also have local effects on DNA methylation different from their global effects.
It’s not just nutrients, or the lack of them, there are more agents leading to abnormal methylation (in certain tissues).
Heredity (it seems epigenetic changes can be inherited), polymorphisms of course, toxins (e.g. cadmium “initially induces DNA hypomethylation, prolonged exposure results in DNA hypermethylation and enhanced DNA MeTase activity”), disease and stress may all change one’s methylation in specific tissues, in specific cells, in specific regions of a gene.
Please correct me if I’m wrong.

I can see that when there’s a need for methylation and one of the factors (mB12, mfolate, etc) is not present in sufficient quantities you’ll have trouble somewhere in your body (resulting in either hypo- or hypermethylation).

As to high levels…
Like B12, methylfolate is rapidly excreted via the kidneys, AFAIK. I have read L-methylfolate is naturally stored in RBC and used by the body when needed.
So will an excess of these two substances lead to methylation problems somewhere? Just having a huge supply does not necessarily mean that things go wrong, does it? Having lots of sugar in the cupboard does not mean you’ll take more than what’s needed when baking a cake.
If an excess does lead to methylation problems: how much is too much, at what dose will these substances become problematic, in what situation can’t the body get rid of them fast enough?
Also, are there any breaks, are there any counteractions the body takes? I surely can imagine that when my kitchen is flooded with sugar, I’ll arrange a relief squad that gets rid of the excess, instead of putting way too much sugar in my cake or baking more cakes than needed…
Rhetorical questions, but if anyone has an answer that would be nice.

You said:
“For some at high levels this [gene silencing] is an essential characteristic. For others there can be too much suppression.”
For some, for others… - yes, I guess it’s difficult to predict how the individual body will response to any level having so many variables (diseases, sensitivities, deficiencies, disorders, genetics, environment).

In short. Based on what I have read thus far about DNA methylation and silencing genes, I am not convinced a high intake of B12 and mfolate has a massive secondary impact, per se. I think it’s rather the opposite that’s true: low intake has massive impact.
(I have not looked into the impact on the production of carnitine, conversion of histidine etc. yet.)
One thing is clear to me though: when it comes to methylation there are many questions unanswered, a lot is unknown.

So I guess a certain well-known local cynic is right:
“In this casino royale of health you place your money and make your bets...”
Or to put it differently, using your words, dbkita:
“You have to find what works for you.”

A higher intake seems to work for me, without creating additional potassium problems; I haven’t changed that K intake one bit since increasing mB12, aB12 and methylfolate.
My sleep’s shorter, but I am rested. Yesterday for the first time since a year or so, I took a 30 minutes’ walk, it turned out to be a bit too much after twenty minutes, then I got so tired and my leg + hip started to hurt. But I turned to my usual self in the evening, so no extra fatigue on top of what I normally experience, a bit tense in the muscles.

But a person whose "wheel" is not stuck, they are far more self-sustaining. Or maybe their wheel was stuck due to ATP issues as Freddd has discussed in his Deadlock quartet thesis and suddenly correcting Krebs flow makes the "water wheel" move again. It is hard to say I think.

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Just had an experience that indicates to me there may be more co-factors involved and that need to be considered. Based on my amino acid profile at the end of last year, I've been taking daily doses of methionine, threonine, and BCAA amino acids as well as carnitine. I'm also taking 35-40 mg injected MB12 daily, 15 mg folate (Deplin), LCF or ALCAR most days, and 60 mg ADB12 daily. The amino acid lab was run before I was quite that high on the quartet dosages and was not taking carnitine at the time.

I also have lyme, and recently have been weathering the spring seasonal flare. I treat it every 5-6 days, and then have a herxhiemer response that typically peaks day 2-3. In January prior to the flare, and while already on the high dosages above, I almost did not have any herxhiemer. In other words either I was not killing much infection and/or was detoxing really well. I think it was the latter because prior to this I had this detox pattern after treatment whether or not it was during the seasonal flare.

Recently the peak of the seasonal flare has hit me hard and I have not been detoxing so well. What happened was rather than the peak on day 2-3 which then resolved, it was peaking but never resolving and was getting worse over a couple of weeks. So I think I had a higher biotoxin load than usual and could not get things moving out well enough.

What I tried which worked REALLY well, was increasing my amino acid doses. So I tripled methionine and threonine, and doubled BCAA for two days, and today just doubled the first two, and took 3 caps of BCAA (base dosage 2 daily). (I'm afraid to stay up over my prescribed dosages too long without checking with my doc.)

It feel like what was happening here was that somehow the "water wheel" got stuck, and needed these aminos to get things going again. The impact was quite dramatic.

I am guessing what was being effected was both in the Krebs cycle and the methionine cycle, and that I was not producing enough glutathione for the heavy biotoxic load I am dealing with right now.

Thanks for mentioning these keywords. DNA methylation and silencing gene expression brought me to a wondrous world I didn’t know. I must say, after googling I’m feeling less worried. Although I did not succeed in doing years of study in one single day, so it could well be I’m missing vital information.

I agree methylation has an impact, but I have difficulty relating massive impacts solely to high intakes of mfolate, mb12 and cofactors. Yes, sure, high intakes have an impact if you have a shortage. But shortage itself may often lead to local or even global hypermethylation. (Hahaha! Hear me, how I sound! Forgive me, just think: the more ignorant, the more arrogant. )

Compared to global hypermethylation global hypomethylation seems to be more risky to me; “genomic instability and loss of heterozygosity” increase the risk of cancer, and genomic demethylation (demethylating drugs) “can have serious side effects and even promote malignant transformations of genes”.

What I learned: global hypomethylation (of the entire genome) often is accompanied by local hypermethylation. And I think (but it could well be I’m confusing things ATM) there’s no such thing as a simple ‘I’m overmethylating’ or ‘I’m undermethylating’ (not alluding to anyone in particular).
When having cancer for instance, there’s often (always?) localised hypermethylation and genome-wide hypomethylation.

Here are some quotes I gathered:

“Undermethylation of the entire genome is referred to as global hypomethylation. Global hypomethylation combined with over methylation of highly select repeated regions of the gene is associated with both aging and cancer. Both undermethylation of tumor-causing genes, where the genes are not turned off, and overmethylation of tumor-suppressing genes, where the genes are turned off, contribute to cancer development.”
“Folate deficiency has been shown to result in both hypo- and hyper–gene-specific methylation. (…) However, with continued folate deficiency, an increase in both p53 and genome-wide methylation was seen.”
“Selenium deficiency decreased DNA methylation in Caco-2 cells and in rat liver and colon. In contrast, vitamin C deficiency has been associated with DNA hypermethylation in lung cancer cells.”
“Retinoic acid [excess] leads to global hypomethylation but region-specific hypermethylation”

What’s causing changes in methylation? Well, IMHO it definitely isn’t just a matter of taking different amounts of B12, methylfolate and cofactors.
“Different nutrients can have different effects on methylation.” Diets high in fat, for instance, negatively affect methylation. I have read that nutrients can also have local effects on DNA methylation different from their global effects.
It’s not just nutrients, or the lack of them, there are more agents leading to abnormal methylation (in certain tissues).
Heredity (it seems epigenetic changes can be inherited), polymorphisms of course, toxins (e.g. cadmium “initially induces DNA hypomethylation, prolonged exposure results in DNA hypermethylation and enhanced DNA MeTase activity”), disease and stress may all change one’s methylation in specific tissues, in specific cells, in specific regions of a gene.
Please correct me if I’m wrong.

I can see that when there’s a need for methylation and one of the factors (mB12, mfolate, etc) is not present in sufficient quantities you’ll have trouble somewhere in your body (resulting in either hypo- or hypermethylation).

As to high levels…
Like B12, methylfolate is rapidly excreted via the kidneys, AFAIK. I have read L-methylfolate is naturally stored in RBC and used by the body when needed.
So will an excess of these two substances lead to methylation problems somewhere? Just having a huge supply does not necessarily mean that things go wrong, does it? Having lots of sugar in the cupboard does not mean you’ll take more than what’s needed when baking a cake.
If an excess does lead to methylation problems: how much is too much, at what dose will these substances become problematic, in what situation can’t the body get rid of them fast enough?
Also, are there any breaks, are there any counteractions the body takes? I surely can imagine that when my kitchen is flooded with sugar, I’ll arrange a relief squad that gets rid of the excess, instead of putting way too much sugar in my cake or baking more cakes than needed…
Rhetorical questions, but if anyone has an answer that would be nice.

You said:
“For some at high levels this [gene silencing] is an essential characteristic. For others there can be too much suppression.”
For some, for others… - yes, I guess it’s difficult to predict how the individual body will response to any level having so many variables (diseases, sensitivities, deficiencies, disorders, genetics, environment).

In short. Based on what I have read thus far about DNA methylation and silencing genes, I am not convinced a high intake of B12 and mfolate has a massive secondary impact, per se. I think it’s rather the opposite that’s true: low intake has massive impact.
(I have not looked into the impact on the production of carnitine, conversion of histidine etc. yet.)
One thing is clear to me though: when it comes to methylation there are many questions unanswered, a lot is unknown.

So I guess a certain well-known local cynic is right:
“In this casino royale of health you place your money and make your bets...”
Or to put it differently, using your words, dbkita:
“You have to find what works for you.”

A higher intake seems to work for me, without creating additional potassium problems; I haven’t changed that K intake one bit since increasing mB12, aB12 and methylfolate.
My sleep’s shorter, but I am rested. Yesterday for the first time since a year or so, I took a 30 minutes’ walk, it turned out to be a bit too much after twenty minutes, then I got so tired and my leg + hip started to hurt. But I turned to my usual self in the evening, so no extra fatigue on top of what I normally experience, a bit tense in the muscles.

Thanks. I’ll do that.

You’re older than adreno?

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SAMe is the ultimate measure of methylation. Efficiency of methylation is measured by SAMe / SAH and other measures. Methylfolate is not only in RBCs. It is in every cell, CNS or periphery and is one of the dominat modalities in the plasma.

If you believe that methylfolate and mb12 working into methionine synthase is the major route to increase SAMe then they will have large impact on methylation. While other factors may alter this, again if your SAMe is high, you will have high levels of methylation as SAMe is a primary methyl donor for many processes.

While I agree that hypomethylation is bad. You have to understand that most of those articles / source especially in regards to cancer research are talking about global levels lower than virtually any experienced by ANY person on these boards. I am almost certain of that. So yes severe hypomethylation is very bad. But I would not discount the concerns with global hypermethylation. And sorry but I choose to disagree based on my knowledge of biochemisty, gene silencing can be excessive and the secondary repercussion are not to be trifled with.

You ask about a level. I think it is dependent on the individual. If you take an amount that causes you to have crippling insomnia for days on end, extraordinary anxiety, muscle pain that cannot be abated at 10 grams of K+ per day, way too much catecholamine production, or excessive runaway inflammation then yeah that is too high an amount in my book. And while some on here have had some success "pushing" through such symptoms, many of us have not even after "pushing" for months or even years. Maybe there is a critical missing cofactor. Maybe it is genetics or epigenetics. Depends on the person.

I am happy that you have not had to supplement K very much at your current or even higher levels. Your genetics / epigenetic profile works well with that. But the levels you quote for yourself would quite simply crush me. I know this based on 2.5 years of methylation treatment and trying many combinations. Remember I don't even have the C677T haplotype. At all. But I do have a homozygous CBS and 4 homozygote BHMT genes. So if I increase methylation much anyways I get whacked with trans-sulfuration overload.

So be thankful you have found levels that work for you. That is great news. But I would be very cautious about applying them as a universal standard. Very cautious. I can't give you an amount of what is low or high except to phrase it in terms of symptoms. In fact no one can or should imo.

I am in my early 40's but my body is very old. Lots of hideous mileage. I look young on the outside for my age (like in my early thirties) but trust me the inside is not young anymore.

SAMe is the ultimate measure of methylation. Efficiency of methylation is measured by SAMe / SAH and other measures. Methylfolate is not only in RBCs. It is in every cell, CNS or periphery and is one of the dominat modalities in the plasma.

If you believe that methylfolate and mb12 working into methionine synthase is the major route to increase SAMe then they will have large impact on methylation. While other factors may alter this, again if your SAMe is high, you will have high levels of methylation as SAMe is a primary methyl donor for many processes.

While I agree that hypomethylation is bad. You have to understand that most of those articles / source especially in regards to cancer research are talking about global levels lower than virtually any experienced by ANY person on these boards. I am almost certain of that. So yes severe hypomethylation is very bad. But I would not discount the concerns with global hypermethylation. And sorry but I choose to disagree based on my knowledge of biochemisty, gene silencing can be excessive and the secondary repercussion are not to be trifled with.

You ask about a level. I think it is dependent on the individual. If you take an amount that causes you to have crippling insomnia for days on end, extraordinary anxiety, muscle pain that cannot be abated at 10 grams of K+ per day, way too much catecholamine production, or excessive runaway inflammation then yeah that is too high an amount in my book. And while some on here have had some success "pushing" through such symptoms, many of us have not even after "pushing" for months or even years. Maybe there is a critical missing cofactor. Maybe it is genetics or epigenetics. Depends on the person.

I am happy that you have not had to supplement K very much at your current or even higher levels. Your genetics / epigenetic profile works well with that. But the levels you quote for yourself would quite simply crush me. I know this based on 2.5 years of methylation treatment and trying many combinations. Remember I don't even have the C677T haplotype. At all. But I do have a homozygous CBS and 4 homozygote BHMT genes. So if I increase methylation much anyways I get whacked with trans-sulfuration overload.

So be thankful you have found levels that work for you. That is great news. But I would be very cautious about applying them as a universal standard. Very cautious. I can't give you an amount of what is low or high except to phrase it in terms of symptoms. In fact no one can or should imo.

I am in my early 40's but my body is very old. Lots of hideous mileage. I look young on the outside for my age (like in my early thirties) but trust me the inside is not young anymore.

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I am sorry, there seems to be a misunderstanding. I was not at all extrapolating my experiences to the rest of the universe, on the contrary.
I was trying to explain why I think people react so differently, to certain amounts of nutrients for instance. It makes perfect sense to me that there are a lot of people who can not tolerate high levels, and based on what I found I would certainly not advise them to try to push their way up. That could be making things worse IMHO.

I was not talking about whole body methylation status.
With global DNA methylation I was refering to the genome. Local, regional DNA methylation is, to my recent understanding, about specific gene(s).

As far as I understand, one part of the genome in a certain type of cells may be hypermethylated while other parts of the same genome may be normal or hypomethylated, or vice versa.
These difference in methylation at micro level are caused by many things, not just changing the intake of b12 and methylfolate, at least that's what I have learned.
A person could have a hypermethylation going on, somewhere in some cells in some tissues, thanks to a toxin, say cadmium, while at the same time having a hypomethylation thanks to a shortage of some nutrient, say zinc, in other areas.
If you simply increase the amount of folate and b12 intake, things would not be solved, would they?
Seeing those differences in methylation - that occur at the same time - I think it's weird to say something like 'I think I am an undermethylator' (which I did say myself in the past).

Let me repeat: I think it’s difficult to predict how the individual body will respond to any level having so many variables (diseases, sensitivities, deficiencies, disorders, genetics, environment) - to which I now would like to add: variables that all affect the methylation in different genes, in different genomes, in different cells, in different tissues in a different direction.
So to me it's obvious that what might be way too low for one might be way too high for another. I think it's impossible to know how the situation at micro level is affected by diseases, sensitivities, deficiencies, disorders, genetics, environment (stress, toxins). Knowing that the situation doesn't have to be the same in every tissue (things can be different in brain, lungs, liver, etc) I think it puts the relevance of a methylation panel quite in perspective.

Sorry but I really do agree with you: no universal standard, everybody should find out for themselves what works best.

I am sorry, there seems to be a misunderstanding. I was not at all extrapolating my experiences to the rest of the universe, on the contrary.
I was trying to explain why I think people react so differently, to certain amounts of nutrients for instance. It makes perfect sense to me that there are a lot of people who can not tolerate high levels, and based on what I found I would certainly not advise them to try to push their way up. That could be making things worse IMHO.

I was not talking about whole body methylation status.
With global DNA methylation I was refering to the genome. Local, regional DNA methylation is, to my recent understanding, about specific gene(s).

As far as I understand, one part of the genome in a certain type of cells may be hypermethylated while other parts of the same genome may be normal or hypomethylated, or vice versa.
These difference in methylation at micro level are caused by many things, not just changing the intake of b12 and methylfolate, at least that's what I have learned.
A person could have a hypermethylation going on, somewhere in some cells in some tissues, thanks to a toxin, say cadmium, while at the same time having a hypomethylation thanks to a shortage of some nutrient, say zinc, in other areas.
If you simply increase the amount of folate and b12 intake, things would not be solved, would they?
Seeing those differences in methylation - that occur at the same time - I think it's weird to say something like 'I think I am an undermethylator' (which I did say myself in the past).

Let me repeat: I think it’s difficult to predict how the individual body will respond to any level having so many variables (diseases, sensitivities, deficiencies, disorders, genetics, environment) - to which I now would like to add: variables that all affect the methylation in different genes, in different genomes, in different cells, in different tissues in a different direction.
So to me it's obvious that what might be way too low for one might be way too high for another. I think it's impossible to know how the situation at micro level is affected by diseases, sensitivities, deficiencies, disorders, genetics, environment (stress, toxins). Knowing that the situation doesn't have to be the same in every tissue (things can be different in brain, lungs, liver, etc) I think it puts the relevance of a methylation panel quite in perspective.

Sorry but I really do agree with you: no universal standard, everybody should find out for themselves what works best.

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Understood.

A good analogy imo is nmda receptor activity. Glycine is an agonist but normally the neurons on a dendritic branch have local control of the localized concentrations of glycine around the nmda receptors. However if the baseline concentration of glycine is too high then local regulation is affected. Then nmda firing escalates so long as glutamate is present.

Now when scientists conduct hypo and hyper methylation experiments they are usuallu going to one extreme or the other. The premise that methylation will switch off some genes and not others is correct. But the assumption that the ones that are silenced as methylation increases are necessarily the ones with bad snps is not plausible imo. As you keep raising the SAMe threshold more and more genes will be silenced though the relationship may be sublinear for some part of the response curve. Beyond that I do not know if and when a saturation point is true reached. I doubt that is the norm unless megadoses are taken. But I would expect the more SAMe the more methylation and the more and more silencing. I never suggested it would suppress equally across the genome. If it did the person would die at some point die and methyfolate and mb12 would be ridiculously regulated. I think it is more common to encounter other side effects much earlier which prevent raising SAMe further. We have discussed those effects ad nausea already.

A good analogy imo is nmda receptor activity. Glycine is an agonist but normally the neurons on a dendritic branch have local control of the localized concentrations of glycine around the nmda receptors. However if the baseline concentration of glycine is too high then local regulation is affected. Then nmda firing escalates so long as glutamate is present.

Now when scientists conduct hypo and hyper methylation experiments they are usuallu going to one extreme or the other. The premise that methylation will switch off some genes and not others is correct. But the assumption that the ones that are silenced as methylation increases are necessarily the ones with bad snps is not plausible imo. As you keep raising the SAMe threshold more and more genes will be silenced though the relationship may be sublinear for some part of the response curve. Beyond that I do not know if and when a saturation point is true reached. I doubt that is the norm unless megadoses are taken. But I would expect the more SAMe the more methylation and the more and more silencing. I never suggested it would suppress equally across the genome. If it did the person would die at some point die and methyfolate and mb12 would be ridiculously regulated. I think it is more common to encounter other side effects much earlier which prevent raising SAMe further. We have discussed those effects ad nausea already.

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I think there is an elephant in the room.

If normal, healthy people don't get into trouble when taking 30 mg of methylfolate or mB12, or even higher, why think of overmethylation when taking crumbs?

If one insists on thinking the effects discussed ad nauseum are due to (over)methylation, I think it makes more sense to think of micro level, to tissue specific differences in methylation already present (hyper/hypo; not necessarily related to mfolate/B12 intakes ) instead of the general amount of SAMe.

But hey, who am I... Besides, my view has no practical use other than stating the obvious every persons's different and the advise ad nauseum to be careful.
I don't wish to irritate anybody by questioning the model used, including myself, so I'll shut up.